Noninvasive High Frequency Oscillatory Ventilation Versus Nasal Intermittent Mandatory Ventilation After Extubation in Neonates

Extubation failure, defined as the need to replace an endotracheal breathing tube after planned removal, is associated with longer hospitalization and increased illness and death in newborns. Noninvasive respiratory support may help newborns transition safely from invasive mechanical ventilation. Nasal intermittent mandatory ventilation (NIMV) delivers regular positive pressure breaths through a nasal interface. Noninvasive high frequency oscillatory ventilation (nHFOV) delivers rapid pressure oscillations through a nasal interface and may improve carbon dioxide removal without requiring synchronization with the newborn's breathing. Although both methods are used in neonatal care, evidence directly comparing them in Pakistan is limited.

NOV-A is a prospective, single center, open label, parallel group superiority randomized clinical trial. It will evaluate whether nHFOV lowers extubation failure compared with NIMV after the first planned extubation. Participants will be assigned in a 1:1 ratio using stratified permuted block randomization based on gestational age. An independent biostatistician will generate the allocation sequence. Allocation will remain concealed in sequentially numbered, opaque, sealed envelopes until eligibility and parental consent are confirmed.

Blinding of the treating clinicians is not possible because the two respiratory support methods use different ventilator settings. To limit bias, prespecified clinical and laboratory criteria will guide decisions to replace the breathing tube. The biostatistician will remain unaware of group identities until the primary analysis is complete.

The primary analysis will follow the intention to treat principle. The treatment effect will be reported as the difference between the proportions of participants requiring replacement of the breathing tube, with a two sided 95% confidence interval. A per protocol analysis will be conducted as a sensitivity analysis. An independent Data Safety Monitoring Board will review safety information after approximately 25%, 50%, and 75% of planned enrollment.

• Noninvasive High Frequency Oscillatory Ventilation (Device), also known as nHFOV, Nasal High Frequency Oscillatory Ventilation: nHFOV will begin immediately after planned extubation and will be delivered through binasal prongs or a nasal mask. Initial mean airway pressure will be 10-12 cm H₂O and may be increased in 1 cm H₂O steps to a maximum of 20 cm H₂O. Initial amplitude will be 15-25 cm H₂O and may be increased in 5 cm H₂O steps to a maximum of 35 cm H₂O. Frequency will be 8-12 Hz, and the inspiratory to expiratory ratio will be 1:1. Oxygen will be adjusted to maintain oxygen saturation between 90% and 95%. Settings will be adjusted according to the participant's clinical condition.
• Nasal Intermittent Mandatory Ventilation (Device), also known as NIMV, Nasal Intermittent Positive Pressure Ventilation, NIPPV: NIMV will begin immediately after planned extubation and will be delivered through binasal prongs or a nasal mask. Positive end expiratory pressure will be 8-12 cm H₂O, and peak inspiratory pressure will be 18-24 cm H₂O. The initial breathing rate will be 30 breaths per minute and may be increased in steps of 5 to a maximum of 50 breaths per minute according to carbon dioxide levels and clinical assessment. Inspiratory time will be 0.5 seconds. Oxygen will be adjusted to maintain oxygen saturation between 90% and 95%. Synchronization will not be used.

Primary outcomes

• Proportion of Participants With Extubation Failure Within 72 Hours [Within 72 hours after planned extubation]: Extubation failure is defined as reintubation and return to invasive mechanical ventilation within 72 hours after planned extubation. Reintubation will be based on at least one prespecified criterion: pH below 7.20 with carbon dioxide above 65 mmHg, need for 60% or more oxygen to maintain the target oxygen saturation, an episode requiring bag mask ventilation, severe respiratory distress or a Silverman Anderson score of 7 or higher or cardiorespiratory arrest requiring cardiopulmonary resuscitation. The outcome will be reported as the number and percentage of participants with extubation failure in each group.

Secondary outcomes

• Proportion of Participants With Clinically Significant Apnea [Within 72 hours after planned extubation]: Clinically significant apnea is defined as three or more breathing pauses within 72 hours after planned extubation that require tactile stimulation. The outcome will be reported as the number and percentage of participants meeting this criterion in each group.
• Proportion of Participants With Feeding Intolerance [Within 72 hours after planned extubation]: Feeding intolerance is defined as two consecutive gastric residual volumes greater than 50% of the previous feed volume, abdominal distension or vomiting that requires enteral feeding to be interrupted or modified for more than 24 hours while the participant is receiving the assigned respiratory support. The outcome will be reported as the number and percentage of participants with feeding intolerance in each group.
• Post-extubation blood pH [At 1, 12, and 24 hours after planned extubation]: Blood pH measured using an arterial or capillary blood gas sample. Values will be recorded and reported separately at 1, 12, and 24 hours after planned extubation. This is a component of the prespecified secondary outcome assessing post-extubation gas exchange and oxygenation.
• Post-extubation partial pressure of carbon dioxide [At 1, 12, and 24 hours after planned extubation]: Partial pressure of carbon dioxide (pCO₂), measured in mmHg using an arterial or capillary blood gas sample. Values will be recorded and reported separately at 1, 12, and 24 hours after planned extubation. This is a component of the prespecified secondary outcome assessing post-extubation gas exchange and oxygenation.
• Post-extubation SpO₂/FiO₂ ratio [At 1, 12, and 24 hours after planned extubation]: The ratio of peripheral oxygen saturation (SpO₂) to the fraction of inspired oxygen (FiO₂). The ratio is unitless. Values will be recorded and reported separately at 1, 12, and 24 hours after planned extubation. This is a component of the prespecified secondary outcome assessing post-extubation gas exchange and oxygenation.

Other outcomes

• Time to Extubation Failure [From planned extubation through 72 hours after extubation]: Time in hours from planned extubation to reintubation and return to invasive mechanical ventilation during the first 72 hours. Participants who are not reintubated within 72 hours will be censored at 72 hours for this time-to-event analysis. Reintubation occurring after 72 hours and within 7 days will be recorded separately as an exploratory outcome.
• Proportion of Participants With Air Leak Syndrome [Up to 7 days after planned extubation or until discontinuation of the assigned nHFOV or NIMV support, whichever occurs first]: The number and percentage of participants who develop an air-leak syndrome after planned extubation while receiving the assigned respiratory support. Air-leak syndromes include pneumothorax, pneumomediastinum, pulmonary interstitial emphysema, pneumopericardium, and subcutaneous emphysema confirmed radiologically or clinically. Events will be recorded until 7 days after planned extubation or discontinuation of the assigned intervention, whichever occurs first.
• Proportion of Participants With Nasal Injury During the Assigned Intervention [Up to 7 days after planned extubation or until discontinuation of the assigned nHFOV or NIMV support, whichever occurs first]: The number and percentage of participants who develop nasal injury while receiving the assigned respiratory support. Nasal injury will be assessed using the Fischer grading system, ranging from grade 0 (no injury) to grade 3 (severe injury). Any injury of grade 1 or higher will be recorded.
• Proportion of Participants Requiring Reintubation After 72 Hours and Within 7 Days [At 7 days after planned extubation]: The number and percentage of participants who remain successfully extubated during the first 72 hours but subsequently require reintubation and return to invasive mechanical ventilation more than 72 hours and within 7 days after planned extubation.
• Duration of Invasive Mechanical Ventilation [From initiation of invasive mechanical ventilation in the NICU until NICU discharge or 44 weeks postmenstrual age, whichever occurs first.]: Cumulative duration of all invasive mechanical ventilation delivered through an endotracheal tube in the NICU, including the initial period before planned extubation and any subsequent periods following reintubation. The durations of all IMV episodes will be summed and reported in days.
• Total Duration of Noninvasive Ventilation [From randomization until discharge from NICU or 44 weeks postmenstrual age, whichever occurs first.]: Cumulative number of days the participant receives noninvasive ventilation after randomization, including the assigned nHFOV or NIMV intervention and any subsequent noninvasive positive-pressure respiratory support. HHHFNC will not be included.
• Total Duration of Respiratory Support [From the first initiation of respiratory support after birth until final discontinuation of all respiratory support or 44 weeks postmenstrual age, whichever occurs first.]: Total number of days from the first use of respiratory support until the participant permanently stops all invasive ventilation, noninvasive ventilation, and supplemental oxygen whether provided in the NICU, step-down unit, or at home. A calendar day during which more than one modality is used will be counted only once.
• Ventilator Free Days After Randomization [From randomization until final hospital disposition or 44 weeks postmenstrual age, whichever occurs first.]: Cumulative number of calendar days after randomization during which the participant is alive and does not receive invasive mechanical ventilation through an endotracheal tube. Days on noninvasive respiratory support, supplemental oxygen, or no respiratory support will be counted as ventilator-free days. Any calendar day during which invasive mechanical ventilation is received will not be counted.
• Proportion of Participants With Severe Intraventricular Hemorrhage [From randomization through final hospital disposition or 44 weeks postmenstrual age, whichever occurs first.]: The number and percentage of participants diagnosed with severe intraventricular hemorrhage, defined as grade III or IV according to the Papile classification, on cranial ultrasound after randomization will be recorded at final hospital disposition. Final hospital disposition is defined as discharge from AKUH, transfer to another facility, leaving against medical advice, or in-hospital death.Cranial ultrasound will be performed as part of routine clinical care for neonates born at <32 weeks' gestation and for neonates born at ≥32 weeks when clinically indicated at the discretion of the treating team. All scans will be reported by a pediatric radiologist. Participants with grade IV intraventricular hemorrhage diagnosed before randomization will be excluded.
• Proportion of Participants With Necrotizing Enterocolitis Stage II or Higher [From randomization until final hospital disposition or 44 weeks postmenstrual age, whichever occurs first.]: The number and percentage of participants diagnosed with definite or advanced necrotizing enterocolitis corresponding to stage II or stage III according to the modified Bell staging criteria after randomization and before final hospital disposition. Final hospital disposition includes discharge, transfer, leaving against medical advice, or in-hospital death. Stage I NEC will not be counted. Surgical treatment, including peritoneal drainage or laparotomy, will be documented.
• Duration of Hospitalization [From admission to Aga Khan University Hospital until final hospital disposition or 44 weeks postmenstrual age, whichever occurs first.]: Total number of days from admission to Aga Khan University Hospital until hospital discharge, transfer to another facility, leaving against medical advice, or in-hospital death.
• Proportion of Participants With All Cause In Hospital Mortality [From randomization until final hospital disposition or 44 weeks postmenstrual age, whichever occurs first.]: The number and percentage of participants who die from any cause after randomization and before final hospital disposition. Participants discharged alive, transferred to another facility, or leaving against medical advice will not be classified as in-hospital deaths.
• Desirability of Outcome Ranking Analysis [From randomization until final hospital disposition or 44 weeks postmenstrual age, whichever occurs first.]: Each participant will be assigned a Desirability of Outcome Ranking (DOOR) at final hospital disposition.Final hospital disposition is defined as discharge from AKUH, transfer to another facility, leaving against medical advice, or in-hospital death. Rank 1: extubation success without any listed major or minor complication. Rank 2: extubation success with minor complications only (nasal injury, feeding intolerance, or clinically significant apnea). Rank 3: extubation success with at least one major complication (grade III-IV intraventricular hemorrhage, stage II-III necrotizing enterocolitis, or air-leak syndrome). Rank 4: reintubation within 72 hours without in-hospital death. Rank 5: in-hospital death. Lower ranks represent better outcomes. The probability that a participant receiving nHFOV has a better outcome than one receiving NIMV will be estimated; a probability >0.50 favors nHFOV.

Sex: All, ages: 1 Day to 18 Weeks

Inclusion Criteria:

* Gestational age at birth ≥26 weeks (inborn or outborn)
* Postmenstrual age <44 weeks at enrollment according to NICU AKUH admission criteria
* Intubation for respiratory distress or respiratory failure
* Intubated for ≥24 hours
* Undergoing first planned extubation
* Meets prespecified extubation readiness criteria
* Written informed consent from a parent or legal guardian

Exclusion Criteria

* Birth weight <500 g
* Major congenital anomaly affecting cardiac or respiratory function
* Upper airway anomaly
* Neuromuscular disorder affecting respiration
* Requirement for surgical intervention during the study period
* Grade IV intraventricular hemorrhage diagnosed before randomization
* Intubation solely for an elective procedure in an otherwise healthy neonate previously breathing room air

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• Ali S Hussain, FCPS Paediatrics, Neonatology, Principal investigator, Aga Khan University